Alzheimer's disease (AD) is a devastating condition of the later decades of life. The prevalence rate in a geographically defined US community were reported by Evans et al. (J. Amer. Med. Assn. 262:2551-56, 1989). Of individuals over 65 years of age, about 10.3% probably had AD. Stratified by decades, the prevalence was 3% for 65-74 years, 18.7% for 75-84 years and 47.2% for 85 and over. With the increasing age of the elderly population, the magnitude of the AD problem is expected to increase.
The criteria for diagnosing AD in the above-mentioned study included 1) a loss of intellectual abilities sufficient to interfere with social or occupational functioning and 2) neuropsychological testing with deficits in two or more areas of cognition. Deficits in neuropsychology tests can be a score of 2 or less on the delayed memory test, a score of 7 or less on the delayed recognition memory span test, or a decrease of two or more between immediate and delayed memory. In addition, there often is impairment in 1) language (a score of 10 or less on naming), 2) spatial ability (score of 5 or less on figure copying) and/or 3) abstraction (score of 6 or less on visual abstraction). The AD diagnosis also requires a history of no sudden onset of symptoms, a clear state of consciousness, and no hearing or visual impairment which could affect test results.
Although the etiology of AD is still being studied, the end-pathology is now well known, neuronal loss and the widespread appearance of neurofibrillary tangles and senile plaques. Some areas of the brain are more heavily involved, such as the temporal cortex and hippocampus, while the occipital cortex and cerebellum are much less affected. Large numbers of reactive microglia in affected regions of AD brains actively express HLA-DR of the major histocompatibility complex (MHC) (McGeer et al., Neurosci. Lett. 79:195-200, 1987). The classical function of HLA-DR is to present foreign antigen to the T-lymphocytic system. Thus, the causative process may be a cell-mediated immune reaction. McGeer et al. analyzed post-mortem brain tissue from AD and normal patients. The differences were striking: In the AD brains, but not the normal brains, activated leukocytes, reactive microglia/macrophages, reactive astrocytes, and T8 and T4 lymphocytes were observed. In both brains, antibody-mediated antigens (HLA-A,B,C) were prominent along the capillary lining cells. The AD-prominent cell types are all important actors in cell-mediated immunity: Reactive microglia express HLA-DR and send signals to activate the T-lymphocytic system, namely T-4 and T-8 lymphocytes. The T-4 cells bind to HLA-DR-expressing cells with antigen and stimulate a further response. The T-8 cells can help destroy cells with this complex and/or inhibit an antibody response. The presence of these various cell types (mainly located in the senile plaques) indicates an active chronic inflammatory process in AD (Itagaki, McGeer and Akiyama, Neurosci. Lett. 91: 259-64, 1988). The antigen which initiates this reaction still is not known; however, amyloid, paired helical filaments (PHF) and A68 are "foreign" proteins found in senile plaques and nowhere else, making them candidates for the causative antigen.
When AD brain and age-matched brain were examined for the presence of several complement components, McGeer et al (Neurosci. Lett. 107:341-346, 1989). reported that the classical complement pathway was activated in AD and that the amyloid deposits appeared to be made of unassembled C7 and C9 complement molecules. The classical pathway is activated by antibodies and a few enzymes, so the etiology is not firmly ascertained. The C9 complement complexes which cause cell lysis and death were found only on dystrophic neurites and neurofibrillary tangles and not on amyloid deposits. This indicates that some protein is being attacked on abnormal neurons.
Because of the apparent chronic immune reaction in AD, McGeer et al. expected to find an increased prevalence of AD in patients with rheumatoid arthritis, another chronic immune reaction. There was actually a relatively low prevalence of both AD and rheumatoid arthritis, which the authors proposed could be caused by rheumatoid patients taking anti-inflammatory agents on a chronic basis, particularly non-steroidal anti-inflammatory drugs (NSAIDs). McGeer et al. hypothesized that such NSAIDs also inhibited an inflammatory process which caused AD in other patients (McGeer et al. The Lancet 335:1037, 1990).
U.S. Pat. No. 5,192,753 to McGeer discloses the use of anti-rheumatoid NSAIDs in the treatment of AD. Five patients clinically diagnosed with early AD were entered into a six-month, open-label study with indomethacin, an NSAID. They were tested before and after by four neuropsychological tests: the Mini Mental Status Exam (MMSE), the Alzheimer Disease Assessment Scale (ADAS), the Boston Naming Test (BNT), and the Token Test (TT). In addition, at three months, the patients also underwent the MMSE and the ADAS. The neuropsychologists performing these tests did not know the patients' treatment regimens. One patient discontinued for failure to take medication. Although most parameters would be expected to deteriorate noticeably in AD patients during the six month interval, there was almost no change on the MMSE, a slight improvement on the BNT, and only slight decrements on the ADAS and the TT. These results were interpreted as successful treatment with an NSAID. In the file history, McGeer disclosed that other AD patients had received prednisone, a steroidal anti-inflammatory, which represented the steroid class. In the file history, McGeer et al. disclosed that prednisone had no effect.
To date, AD has no known prevention or cure. Treatment at this time is still palliative, consisting of proper nutrition, exercise and supervision of daily activity. Medication can help in reducing agitation and behavior problems. Propranolol, pindolol, buspirone and valproate have all been reported to help reduce agitation and aggression. Haloperidol and other high-potency dopamine-blocking agents may be used to control acute behavior disturbances. However, none of the proceesing improve memory or any of the underlying functional problems of AD. A subgroup of patients with AD shows improvement in cognitive and functional measures when treated with tacrine (COGNEX.RTM., Parke-Davis Division of Warner-Lambert, Morris Plains N.J.), a potent centrally active, reversible acetycholinesterase inhibitor (Kaplan and Sadock, eds., CONCISE TEXTBOOK OF CLINICAL PSYCHIATRY, Williams & Wilkins, Baltimore, Md., 1996, p. 592)
What is needed is a drug which helps maintain or improve the mental status of AD patients, particular those functions associated with memory.